A New Tool to Confront Lung Cancer

Only 15% of patients with squamous cell lung cancer – the second most common lung cancer – survive five years past diagnosis. Little is understood about how the deadly disease arises, preventing development of targeted therapies that could serve as a second line of defense once standard chemotherapy regimens fail.

Published online in Cell Reports on June 19, Huntsman Cancer Institute investigators report that misregulation of two genes, sox2 and lkb1, drives squamous cell lung cancer in mice. The discovery uncovers new treatment strategies, and provides a clinically relevant mouse model in which to test them.

“This is the most exciting thing we’ve done,” said senior author Trudy Oliver, Ph.D., an assistant professor of oncological sciences at the University of Utah and Huntsman Cancer Institute investigator. “Now that we have a model it unleashes so many questions we can ask to gain a better understanding of the disease.”

By definition, tumors are groups of cells that are out of control. As a result, they acquire mutations, only some of which drive properties – such as excess growth and motility – that make cells cancerous. The trick for developing targeted therapies is to distinguish the “driver” from “passenger” mutations that are merely along for the ride.

Call it guilt by association, but Oliver’s team honed in on drivers of squamous cell carcinoma (SCC) of the lung by poring through documented gene abnormalities found in human SCCs. Sox2 was designated a prime candidate based on its overexpression in 60-90% of SCCs, and a frequent early appearance during tumor formation, suggesting it could be an initiator of cancer. Tumor suppressor genes were also candidates, including Lkb1, which is mutated in 5-19% of SCCs.

While disruption of either gene alone failed to trigger cancer, combining overexpression of sox2 in the lung with loss of lkb1 led to frequent development of lung SCC in mice.

“A pathologist looking under the microscope at our tumors would not know it’s from the mouse,” said Oliver. “They visually look like human tumors, and then when we stain them for biomarkers of the human disease, our mouse tumors light up for those markers.”

Unlike most previously existing lung SCC mouse models that develop multiple tumor types, the sox2/lkb1 model generates SCC exclusively. Combine this with the fact that it was created based on patient data makes the model clinically relevant, and well poised for testing novel targeted therapies.